Sexual transmission is the predominant mode for epidemic spread of human immunodeficiency virus (HIV). In man, sexual transmission is correlated with a change in the virus population. The newly infected recipient manifests only a portion of the complex virus population found in the donor. Similar data were obtained in animal infection experiments wherein juvenile male rhesus monkeys were inoculated intrarectally with simian immunodeficiency virus (SIV). Again, the population of viruses in the newly infected recipient was much different than the complex population in the inoculum. Current data from animal and human studies favor selection among individual viruses as the model for mucosal infection and implicate virus structural elements as determinants of transmission efficiency. The objectives of this proposal are to identify virus sequences associated with efficient mucosal transmission and to establish quantitative differences in mucosal infectivity for molecularly cloned viruses in the rhesus monkey. We identified numerous envelope gene and long terminal repeat (LTR) SIV sequences in rhesus monkeys that were infected following atraumatic intrarectal inoculation. We will use cloned envelope and LTR sequences that were correlated specifically with intrarectal transmission, to construct recombinant chimeric viruses. Individual infectious molecular clones of SIV will be characterized for in vitro properties and cellular tropism. Based on these criteria, we will select viruses with unique properties and study their ability to cross the mucosal barrier in rhesus monkeys. One recombinant virus that is identified as efficiently transmitted across the mucosa and another that is inefficiently transmitted by this route will be compared in a dose ranging study to provide a quantitative definition of mucosal infectivity. Quantitative infectivity studies are needed to understand the phenomenology of sexual transmission in man. It is possible that individual virus strains present at very low frequency in the natural inoculum, might still mediate infection because of their enhanced efficiency for mucosal transmission. In this circumstance, the efficient viruses must be high priority targets for vaccine development and, because these viruses are present in small numbers, transmission may be preventable by prior vaccination. Identification of common genotypes or phenotypes of efficiently transmitted viruses are of immediate interest for understanding the rates of sexual transmission in man. Current studies examine the complexity of HIV-1 sequence present in genital fluids and organs of reproduction and it is crucial to focus these studies on the fraction of viruses that present the greatest risk. Basic knowledge of virus structural elements involved in sexual transmission will also facilitate studies of the cellular and molecular mechanisms that regulate infection efficiency in the living host.
